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MCD Haematology > Haemostasis > Flashcards

Haemostasis Flashcards

1
Q

What is the initial response to injury?

A

Vessel constriction

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2
Q

What are the main steps in haemostats plug formation?

A

Vessel constriction
Formation of an unstable platelet plug
Stabilisation of plug with fibrin
Dissolution of clot and vessel repair

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3
Q

What vessels is vessel constriction particularly important in?

A

Small blood vessels

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4
Q

What are the two important steps in the formation of an unstable platelet plug?

A

Platelet adhesion to the damaged vessel wall

Platelet aggregation

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5
Q

What would happen if you didn’t have stabilisation of the platelet plug with fibrin?

A

It would quickly break down

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6
Q

What system is involved in the breakdown of the platelet plug?

A

Fibrinolytic system

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7
Q

What is the role of endothelial cells?

A

Create a barrier between blood and procoagulant sub endothelial structures

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8
Q

Why is collagen in the subendothelial layer important?

A

It is important in platelet interaction with the damaged blood vessel

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9
Q

What is the other important factor?

A

Tissue factor

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10
Q

Where is tissue factor normally found?

A

On surface of cells that underlie blood vessels but it isn’t normally present within the circulation itself

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11
Q

What do endothelial cells produce that is important for haemostasis?

A

Prostacyclin
Thrombomodulin
Von Willebrand Factor
Plasminogen activator

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12
Q

What is von Willebrand factor important for?

A

Initial platelet interaction with the damaged area

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13
Q

What are plasminogen activators involved in?

A

Breakdown of clots

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14
Q

Where do platelets originate?

A

In megakaryocytes

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15
Q

What are megakaryocytes formed from?

A

Blood stem cells

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16
Q

What does the maturation of megakaryocytes in the bone marrow lead to?

A

Granulation- important for platelet formation

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17
Q

What do platelets not have?

A

A nucleus

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18
Q

What types of storage granule are there in platelets?

A

Granules containing ADP (very important for function)

Alpha granules- storage for proteins including factor V and vWF

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19
Q

When are these factors released?

A

When platelets are activated

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20
Q

What happens when the endothelial monolayer is damaged?

A

Subendothelial structures are exposed- collagen

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21
Q

Why is collagen important?

A

It is the molecule that platelets initially react with

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22
Q

What are the two ways that platelets can bind to collagen?

A

Von Willebrand factor can bind to the collagen at the site of damage and unfolds so that it can capture platelets via glycoprotein 1b receptors
They can also bind directly to the collagen via glycoprotein 1a receptors

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23
Q

What happens once the platelet has been recruited and receptors engaged?

A

The receptors signal inside the cell to release the ADP from the storage granules and to synthesise thromboxane, these agents are then released

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24
Q

What happens once these agents are released?

A

They bind to receptors on platelet surface and activate them making them change shape and release its storage granules

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25
Q

What happens once the platelets have been activated?

A

They aggregate and form a haemostatic plug

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26
Q

What helps the platelets to aggregate?

A

Once the platelets have been activated, glycoprotein 2b/3a receptors become available which can bind to fibrinogen and helps the platelets clump together

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27
Q

Clinically why are the glycoprotein 2b/3a receptors important?

A

Therapeutic target

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28
Q

What can also activate platelets?

A

Thrombin

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29
Q

What does platelet activation lead to activation of?

A

Prostaglandin metabolism

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30
Q

What enzyme is used in prostaglandin metabolism to mobilise membrane phospholipid and convert it into arachidonic acid?

A

Phospholipase

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31
Q

As well as platelets, where else does prostaglandin metabolism occur?

A

Activated endothelial cells

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32
Q

In platelets and endothelial cells, you will find COX, what effect does it have?

A

It converts arachidonic acid to endoperoxides

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33
Q

What happens in platelets after endoperoxides are formed?

A

Thromboxane synthetase converts endoperoxides to thromboxane

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34
Q

What is thromboxane?

A

Potent inducer of platelet aggregation

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35
Q

What happens in endothelial cells after endoperoxides are formed?

A

Prostacyclin synthesise converts endoperoxides to prostacyclin

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36
Q

What is prostacyclin?

A

An important regulator of haemostasis that is constantly synthesised by endothelial cells

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37
Q

How does aspirin work?

A

It is a COX inhibitor

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38
Q

What are the two main type of anti platelet agents?

A

ADP receptor antagonist- prevent activation

COX 1 antagonists

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39
Q

What examples are there of ADP receptor antagonists?

A

Clopidogrel

Prasugrel

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40
Q

What examples of GPIIb/IIIc antagonists are there?

A

Abciximab, tirofiban and eptifibatide

41
Q

What are the three main tests to monitor platelets and their function?

A

Platelet count- most important
Bleeding time
Platelet aggregation

42
Q

What is the normal range of platelets?

A

150-400 x 10^9/L

43
Q

What is spontaneous bleeding often caused by?

A

Autoimmune thrombocytopenia

44
Q

What is leukaemia?

A

The bone marrow is populated with leukaemia cells so it crowds out the megakaryocytes so the platelets aren’t produced in sufficient numbers

45
Q

What is bleeding time used to check?

A

Platelet-vessel wall interaction when platelet count is normal e.g. renal disease

46
Q

How is bleeding time test carried out?

A

Cuff with 40mm pressure is fitted then you make a standardised incision and record the bleeding time which is normally 3-8 minutes

47
Q

Why is the bleeding test not popular anymore?

A

Very invasive

48
Q

What is the platelet aggregation test used to check?

A

Functional defect of platelets e.g. vWF disease and inherited platelet defects

49
Q

How is the platelet aggregation test carried out?

A

Their platelets are stimulated with ADP/thromboxane/collagen to stimulate their function

50
Q

Where are most coagulation proteins synthesised?

A

The liver

51
Q

Where is vWF synthesised?

A

Endothelial cells and megakaryocytes

52
Q

Where is factor V synthesised?

A

Megakaryocytes

53
Q

What are the two main routes of coagulation?

A

Extrinsic and intrinsic pathways

54
Q

What is the main factor involved with tissue factor?

A

VIIa

55
Q

How does factor VII work?

A

It circulates partially activated and then it recognises tissue factor and triggers coagulation

56
Q

What does tissue factor activate and how does each conversion compare?

A 
9->9a = Takes more time but produces more thrombin
10->10a = Quicker
57
Q

Which reactions involve phospholipid?

A

X -> Xa

Prothrombin -> Thrombin

58
Q

Where do the reactions involving phospholipid therefore take place?

A

Surface of the activated platelet

59
Q

What are the roles of factor 8 and 5?

A

Accelerating factors- catalysts

60
Q

What activates factor 8 and 5?

A

Trace amounts of thrombin

61
Q

For 9a to activate 10 to 10a, they must get close in proximity, how does the platelet facilitate this?

A

They both bind to the surface of platelet, mediated by calcium ions and factor 8a brings the two close together so that factor 9a can proteolytically activate factor 10 to 10a

62
Q

What is the net outcome effect of the platelets facilitating the conversion of 10 to 10a and prothrombin (2) to thrombin (2a)?

A

10000 fold increase in rate of thrombin generation

63
Q

What is the net outcome effect of the platelets facilitating the conversion of 10 to 10a and prothrombin (2) to thrombin (2a)?

A

10000 fold increase in rate of thrombin generation

64
Q

What do clotting factors made in the liver (important ones are 2, 7, 9 and 10) have a cluster of?

A

Glutamic acid

65
Q

Why is this glutamic acid important?

A

It is recognised by an enzyme in the liver and this is converted in a post-translational modification in the presence of vitamin K to gamma-carboxyglutamic acid so an extra carboxyl group is added

66
Q

What can happen once the extra carboxyl group has been added?

A

Calcium can facilitate the binding of the gamma carboxyglutamic acid to the activated platelet membrane phospholipid which allows clotting factors to localise on surface of the platelet

67
Q

What is this gamma carboxylation dependent on?

A

Vitamin K in the liver

68
Q

How does warfarin work?

A

It inhibits vitamin K and stops the gamma carboxylation taking place so clotting factors are unable to bind to the surface of the platelets

69
Q

What enzyme carries out the gamma carboxylation?

A

Vitamin K epoxide reductase

70
Q

What is warfarin used for?

A

It used to be the most widely used anticoagulant in the country, it is used for long term anticoagulation following venous thrombosis and for treatment of atrial fibrilation

71
Q

What is the main inhibitor of coagulation enzymes?

A

Antithrombin

72
Q

What does heparin do?

A

It potentiates the action of antithrombin- makes it work more effectively at directly inhibiting these clotting enzymes

73
Q

What is heparin used for?

A

Immediate anticoagulation in venous thrombosis and pulmonary embolism

74
Q

How does antithrombin work?

A

It inhibits coagulation factors such as factor 10a and thrombin

75
Q

Where is antithrombin found?

A

It is a protein that circulates in quite high concentrations in the blood

76
Q

How does antithrombin inhibit the coagulation factors?

A

It has a reactive loop that irreversibly blocks the active site of coagulation factors

77
Q

How does heparin work in general?

A

It is a linear negatively charged polysaccharide and it works by binding to antithrombin, it then makes the inhibitor of factor 10a and thrombin occur faster

78
Q

How does heparin inhibit thrombin?

A

It binds to antithrombin and changes the position of the reactive loop and makes the inhibition occur faster

79
Q

What is the difference between thrombin and 10a in terms of being inhibited by heparin?

A

With 10a, a relatively short section of heparin chain is sufficient to make antithrombin block 10a more quickly but thrombin requires a large heparin chain

80
Q

What are the two forms of heparin?

A

Low molecular weight heparin- favours inhibition of factor 10a
Standard/unfractionated heparin= inhibits either of the two

81
Q

What are the three laboratory tests for blood coagulation?

A

Activated partial thromboplastin time (APTT)
Prothrombin time (PT)
Thrombin clotting time (TCT)

82
Q

How does the activated partial thromboplastin time test work?

A

Coagulation is triggered by activation of factor 12 and the test measures clotting time

83
Q

What is the activated partial thromboplastin time used to detect?

A

Abnormalities in intrinsic and common pathways

84
Q

How does the prothrombin time test work?

A

Tissue factor is added to trigger the extrinsic pathway

85
Q

What does prothrombin time test detect abnormalities with?

A

Extrinsic and common pathways

86
Q

What is thrombin clotting time used to detect?

A

Abnormality in fibrinogen to fibrin conversion

87
Q

What tests are used together to screen for causes of bleeding disorders?

A

Activated partial thromboplastin time and prothrombin time

APTT + PT

88
Q

What is the main individual use of activated partial thromboplastin time (APTT)?

A

Monitor heparin therapy for thrombosis

89
Q

What is the main individual use of prothrombin time (PT)?

A

Monitor warfarin treatment in thrombosis

90
Q

What is plasminogen?

A

Plasma protein

91
Q

What is tissue plasminogen activator produced by?

A

Endothelial cells

92
Q

What is the normal interaction between plasminogen and tissue plasminogen activator?

A

There is none

93
Q

When is there an interaction between plasminogen and tissue plasminogen activator?

A

When a fibrin clot forms, these two proteins assemble on the surface of the clot and plasminogen is converted to plasmin by tPA

94
Q

What does plasmin do after being formed?

A

Breaks down the clot

95
Q

What is tissue plasminogen activator and bacterial activator streptokinase commonly used for?

A

Therapeutic thrombolysis of myocardial infarction

96
Q

Why doesn’t blood clot completely when activated?

A

2 anticoagulant pathways:
Antithrombin
Protein C anticoagulant

97
Q

What is antithrombin and how does it work?

A

It is a plasma protein and it directly inhibits clotting factors- IXa, Xa and thrombin

98
Q

What is the anticoagulant role of thrombin?

A

It binds to thrombomodulin on the surface of the endothelial cell

99
Q

What does thrombin binding to thrombomodulin cause?

A

Thrombin activates protein C which, along with cofactor protein S, inactivates factor 5a and factor 8a

MCD Haematology (11 decks)

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